Bupropion is an antidepressant chemically unrelated to tricyclics, tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or other known antidepressant agents. The drug resembles a psycho stimulant in terms of its neurochemical and behavioral profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Its structure closely resembles that of diethylpropion and it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride and by its generic name amfebutamone hydrochloride. Bupropion hydrochloride is commercially available as an immediate release form (Wellbutrin®) and a sustained release form (Wellbutrin® SR and Zyban®). Both Wellbutrin® SR and Zyban® are chemically and pharmaceutically identical.
The neurochemical mechanism of the antidepressant effect of bupropion is not well known. Bupropion does not inhibit monoamine oxidase. Bupropion affects chemicals within the brain that nerves use to send messages to each other. These chemical messengers are called neurotransmitters. The neurotransmitters that are released by nerves are taken up again by the nerves that release them for reuse (This is referred to as reuptake). Many experts believe that depression is caused by an imbalance among the amounts of neurotransmitters that are released. It is believed that bupropion works by inhibiting the reuptake of the neurotransmitters dopamine, serotonin, and norepinephrine, an action which results in more dopamine, serotonin, and norepinephrine made available to transmit messages to other nerves. Accordingly, bupropion is unique in that its major effect is on dopamine, an effect, which is not shared by the SSRIs (e.g. paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®)) or the tricyclic antidepressants or TCAs (e.g. amitriptyline (Elavil®), imipramine (Tofranil®), desipramine (Norpramin®)).
Wellbutrin® and Wellbutrin® SR are used for the management of depression. Zyban® has been approved as an aid to patients wanting to quit smoking. Wellbutrin®, the immediate release formulation of bupropion, is dosed three times a day, preferably with 6 or more hours in between doses. For patients requiring more that 300 mg bupropion a day, each dose should not exceed 150 mg. This requires administration of the tablets at least 4 times a day with at least 4 hours in between doses. The immediate release formulation results in more than a 75% release of the bupropion into the dissolution media in about 45 minutes, and one of the major side effects of bupropion has been the incidence of seizures, which in part appears to be strongly associated with the immediate release of the bupropion into the system. Accordingly, sustained release products were developed to avoid the incidence of seizures. The sustained release products are dosed twice daily.
In general, patient compliance is a problem with medications that require a multiple dosing regimen and is especially problematic with depressed individuals. While sustained release formulations have simplified the dosing regimen and increased patient compliance, there is still room for further simplifying the dosing regimen and further improving patient adherence to the dosing regimen. The development of an approved stable once daily modified-release bupropion formulation would be an advance in the art.
Sustained release tablet forms of bupropion have been described in the prior art. U.S. Pat. No. 4,687,660 discloses a tablet formed of a core and a coating, where the core comprises bupropion hydrochloride together with excipient(s) and optionally an osmotic enhancing agent and where the coating comprises a water-insoluble, water-permeable film-forming polymer (such as cellulose acetate), a pore-forming agent (such as impalpable lactose and sodium carbonate), and optionally a so-called water-permeability enhancing agent (such as polyethylene glycol) and again optionally a plasticizer.
U.S. Pat. Nos. 5,358,970 and 5,427,798 describe a sustained release formulation of bupropion hydrochloride based on matrix technology. The term matrix refers to a tablet where the drug is embedded in an excipient that makes a non-disintegrating core called a matrix. Drug diffusion occurs through this core. As bupropion hydrochloride is unstable, the product described in the above two patents requires a stabilizer to achieve sufficient stability. This stabilizer is an acidic compound, preferably cysteine hydrochloride. The major disadvantage of matrix systems is that they generally display a first order release profile. That is, initially drug particles located at the surface of the tablet will be dissolved and drug released rapidly. Thereafter, drug particles at successively increasing distances from the surface of the tablet will be dissolved and released by diffusion in the pores to the exterior of the tablet. Thus, the diffusion distance of the drug will increase as the release process proceeds. It is normally preferred that a zero order or near zero order release profile is obtained rather than a first order release profile. Zero order release system provides a constant rate of drug release over a defined period of time. It is used primarily for drugs with short half-lives so that constant blood levels of the active drug compounds can be maintained with fewer doses.
U.S. Pat. No. 6,589,553 and International Publication No. WO 02/062299 purportedly describes a once daily capsule formulation with two populations of coated pellets, each of which release bupropion hydrochloride at a different pH. One population of pellets is coated to release the drug at a pH corresponding to about 4.8 and lower. The release of the drug from this population of pellets is expected to occur in the upper GI tract. The other population of pellets is coated to release the drug at a pH of 7 and above. The release of bupropion from this population is expected to occur in the lower GI tract. In one example shown, the relative bioavailability of bupropion to Zyban® was only 40% in terms of Cmax ratio and only 80% in terms of AUC0-inf ratio. In another example shown, the relative bioavailability of bupropion to Zyban® was only 48% and 59% in terms of Cmax and AUC0-inf. The references further describe the introduction of a third population of uncoated active pellets, which purportedly result in a further modification and improvement of the bupropion release. Based on the mean plasma concentration-time profile shown in FIGS. 3 and 4 of these references it is not readily apparent that the introduction of the uncoated active pellets would result in a once daily bioequivalent formulation (reference product is Zyban®). Also, neither one of the two references present any drug stability data.
U.S. Pat. No. 6,033,686 describes a controlled release tablet, free of stabilizer and free of pore forming agent comprising a core consisting essentially of bupropion hydrochloride, a binder and a lubricant; and a coating comprising a water-insoluble, water-permeable film forming polymer, a plasticizer and a water-soluble polymer. The product resulting from the '686 patent is a twice daily product.
U.S. Pat. Nos. 6,096,341 and 6,143,327 both relate to a delayed release formulation of bupropion hydrochloride. The '341 patent provides for a controlled release tablet, free of stabilizer and free of pore forming agent comprising a core consisting essentially of bupropion hydrochloride, a binder and a lubricant; and a coating consisting essentially of a water-insoluble, water-permeable film forming polymer, a plasticizer and a water-soluble polymer. The '327 patent provides for a controlled release tablet, free of stabilizer and free of pore forming agent comprising a core consisting essentially of bupropion hydrochloride, a binder and a lubricant; and a control-releasing coat consisting essentially of a water-insoluble, water-permeable film forming polymer, a plasticizer and a water-soluble polymer and a second coat consisting essentially of a methacrylic polymer and a plasticizer. The formulation as described in the '327 patent does not however, conform to the FDA's guidelines for bioequivalency (see Example 8 herein).
There is currently no approved commercially available stable once daily bupropion dosage form. Accordingly, there is a need for a stable once daily bioequivalent formulation of bupropion or a pharmaceutically acceptable salt thereof.